The insulin-like growth factor-I receptor (IGF-IR) plays an important role in promoting the growth of cancers by stimulating malignant cell proliferation and transformation, and inhibiting apoptosis. We identified suppressor of cytokine signaling (SOCS)-3 as an intracellular binding partner of the IGF-IR. In human colon cancer Caco-2 cells, the IGF-IR and IGF-II are expressed at high levels and SOCS-3 is significantly induced by IGF-I stimulation. SOCS-3 protein is heavily phosphorylated in serine residues and this serine phosphorylation is noticed with or without IGF-I stimulation. SOCS-3 protein localized mostly in the cytoplasm and IGF-I stimulation results in both nuclear and cytoplasmic localization. Moreover, SOCS-3 protein is ubiquitinated in mammalian cells. These results suggest that SOCS-3 protein may play regulatory roles in IGF-IR signaling. SOCS-3 has been shown to be a negative regulator of interleukin (IL-2, IL-6), growth hormone, prolactin, insulin and leptin receptor signaling pathways. The primary goal of this study is to define the function of SOCS-3 in IGF-IR signaling in malignant cells. We hypothesize that SOCS-3 may play a negative regulatory role in IGF-IR signaling in malignant cells. To test this hypothesis we formulated the following specific aims: 1) to identify which signal transduction pathway(s) of the IGF-IR might be affected by the IGF-IR-SOCS-3 interaction, 2) to determine whether this interaction alters kinase activity or stability of the receptor, and 3) to determine the mechanisms by which IGF-IR-SOCS-3 interaction might interfere with IGF-I stimulated proliferation, invasion and inhibition of apoptosis in malignant cells. Our long-term goal is to investigate the negative regulation of the IGF-IR signaling by SOCS-3, a potentially novel mechanism for growth resistance and cancer prevention.